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Pathophysiology of sepsis

William J Sibbald, MD, FRCPC

Remi Neviere, MD Jan 6, 2000

The normal host response to infection is a complex process which serves to

localize and control bacterial invasion and to initiate repair of injured tissue. This
inflammatory process is normally accompanied by activation of circulating and
fixed phagocytic cells and by generation of proinflammatory and antiinflammatory
mediators. Sepsis results when the prerequisite inflammatory response to infection
becomes generalized and extends to involve otherwise normal tissue which is
usually remote from the initial site of injury or infection.

This card will discuss the current understanding of the pathophysiology of sepsis,
including mechanisms of multiple organ system dysfunction. Additional issues
related to sepsis and its management are discussed elsewhere. (See "Sepsis and the
systemic inflammatory response syndrome: Definitions and prognosis" and see
"Management of septic shock-I").

DEFINITION — Sepsis is a clinical syndrome which complicates severe infection

and represents the systemic response to the infection. It is characterized by
systemic inflammation and widespread tissue injury. The clinical definition
requires clear evidence of infection plus the clinical signs of the systemic
inflammatory response syndrome (SIRS). SIRS is a widespread inflammatory
response to a variety of severe clinical insults. This syndrome is clinically
recognized by the presence of two or more of the following:

• Temperature >38ºC or <36ºC

• Heart rate >90 beats/min
• Respiratory rate >20 breaths/min or PaCO2 <32 mmHg
• WBC >12,000 cells/mm3, <4000 cells/mm3, or >10 percent immature (band)

(See "Sepsis and the systemic inflammatory response syndrome: Definitions and

PATHOGENESIS — Sepsis has been referred to as a process of malignant

intravascular inflammation [1].
• It is considered malignant because it is uncontrolled, unregulated, and self-

• It is considered intravascular because it represents the blood-borne spread of

what is usually a cell-to-cell interaction in the interstitial space.

• It is considered inflammatory because all characteristics of the septic response

are exaggerations of the normal inflammatory response.

When tissue is injured or infected, there is simultaneous release of

proinflammatory and antiinflammatory elements. The balance of these contrasting
signals helps to facilitate tissue repair and healing. However, remote tissue injury
may ensue when this equilibrium in the inflammatory process is lost, and these
mediators exert systemic effects [2].

• The significant consequences of a systemic proinflammatory reaction include

endothelial damage, microvascular dysfunction, and impaired tissue oxygenation
and organ injury.

• The significant consequences of an excessive antiinflammatory response

include anergy and immunosuppression.

• In addition, pro- and anti-inflammatory processes may interfere with each

other, creating a state of destructive immunologic dissonance [3].

Sepsis may therefore be described as an autodestructive process that permits the

extension of a normal pathophysiologic response to infection to involve otherwise
normal tissue. This can result in the multiple organ dysfunction syndrome

The outcome from sepsis due to serious infection has a number of determinants.
The most important of these factors are host defense mechanisms, the environment,
and the specific bacteria involved (show figure 1). A particularly high fatality rate
has been associated with bloodstream infections due to Candida species and
Pseudomonas aeruginosa [4]. Specific etiologic organisms also contribute to
morbidity; for example, infections with Candida species, Pseudomonas aeruginosa,
Klebsiella pneumoniae, Enterobacter, and Serratia marcescens are predictors of the
clinical parameters associated with shock.
Before discussing the types, mediators, and mechanisms of sepsis-induced organ
dysfunction, this card will review the normal inflammatory response.

Normal inflammatory processes — Inflammation is normally intended to be a local

and contained response to infection. While initiating insults may be numerous, the
inflammatory processes are qualitatively similar. At the site of injury, the
endothelium expresses adherence molecules to attract leukocytes. At the same
time, polymorphonuclear leukocytes (PMNs) are activated and express adhesion
molecules which cause their aggregation and margination to the vascular
endothelium. A prerequisite for subsequent phagocytosis of invading bacteria and
debris from injured tissue is diapedesis and then migration of these PMNs to the
site of injury [5].

The release of mediators by PMNs at the site of injury or infection is responsible

for the cardinal signs of local inflammation:

• Local vasodilation and hyperemia

• Increased microvascular permeability, resulting in protein-rich edema.

The primitive, but effective, local inflammatory processes (adherence, chemotaxis,

phagocytosis, bacterial killing) are highly regulated at various levels, mainly
through the production of cytokines by macrophages. Once a macrophage has been
triggered and activated during the invasion of tissue by bacteria, it secretes
cytokines (eg, tumor necrosis factor, interleukins) and other mediators into the
cell's microenvironment.

Tumor necrosis factor (TNF) release becomes self-stimulating (an autocrine

process), and cytokine levels are further increased by the release of other
inflammatory mediators, including interleukin-1, platelet activating factor, IL-2,
IL-6, IL-8, IL-10, interferon, and eicosanoids. This leads to continued activation of
PMNs, macrophages and lymphocytes. In addition, the proinflammatory mediators
recruit more PMNs and macrophages (a paracrine process). The net effect is
clearing of bacteria and debris, which is followed by tissue repair.

In some cases, mediator release exceeds the boundaries of the local environment.
This may lead to a more generalized response that affects otherwise normal tissue
(show figure 2). This process is referred to as sepsis when it occurs in association
with infection, and as SIRS when it is induced by noninfectious conditions, such as
pancreatitis, severe trauma, and aspiration.
SPECIFIC ORGAN INVOLVEMENT — It is not uncommon for organ
dysfunction or organ failure to be the first clinical sign of sepsis. No organ system
is immune from the consequences of the inflammatory excesses of sepsis, but the
following are primarily involved

The circulation — Significant derangement in metabolic autoregulation, ie, the

process which matches oxygen availability to changing tissue oxygen needs, is
typical of sepsis. Vasoactive mediators that are released with inflammation cause
an appropriate vasodilation and an increase in microvascular permeability at the
site of infection. Among these mediators are the vasodilators prostacyclin and
nitric oxide (NO), which are produced by endothelial cells.

NO is believed to play a central role in the vasodilation accompanying septic shock

[6]. Induction of an inducible form of NO synthase can be demonstrated after
incubating vascular endothelium and smooth muscle with endotoxin. When this
process extends to involve the systemic circulation, mediators like NO depress the
control mechanisms that match oxygen delivery to oxygen needs at all the central,
regional, and microregional levels of the circulation.

A potential factor that may contribute to persistence of vasodilation is impaired

compensatory secretion of antidiuretic hormone (vasopressin). A 1997 report
found that plasma vasopressin levels were much lower in 19 patients with septic
shock than in 12 with cardiogenic shock who had similar systemic blood pressures
(3.1 versus 22.7 pg/mL) [7]. Why this might occur is not clear. However, it may be
clinically relevant since vasopressin infusion raised the blood pressure from 92/52
to 146/66, even in patients already treated with intravenous catecholamines.

• In the central circulation, changes in both systolic and diastolic ventricular

performance are early manifestations of sepsis. Nevertheless, ventricular function
may initially be able to increase the cardiac output through use of the Frank
Starling mechanism. This increase in output is necessary to maintain the blood
pressure in the presence of the systemic vasodilation which complicates sepsis.
Patients with preexisting cardiac disease may be unable to increase their cardiac
output appropriately. This may be a particular problem in elderly subjects.

• In the regional circulation, the vascular hyporesponsiveness induced by sepsis

leads to considerable heterogeneity in the normal distribution of systemic blood
flow among organ systems. As an example, sepsis interferes with the normal
ability to redistribute blood flow from the splanchnic organs to the core organs
(heart and brain) when oxygen delivery is depressed [8].
• The microcirculation is a key (if not the most important) target organ for injury
in the sepsis syndrome. Sepsis is associated with a decrease in the number of
functional capillaries (capillarity), which causes an inability to extract oxygen
maximally (show figure 3) [9,10]. Depressed capillarity includes "no flow" and
excessive intermittent flow capillaries. These may be due to extrinsic compression
of the capillary by tissue edema, endothelial swelling, and plugging of the capillary
lumen by leukocytes or red blood cells (which lose their normal deformability
properties in sepsis). In one clinical study in patients with hyperdynamic sepsis,
reflectance spectrophotometry demonstrated decreased oxygenation and tissue
hemoglobin concentration in the presence of severely hypoxic microdomains [11].

Panendothelial activation in sepsis also leads to widespread tissue edema, which is

rich in protein. Other adverse effects of endothelial dysfunction in sepsis include
impaired anticoagulant properties and upregulation of adhesion molecules.

Hypotension is the most severe expression of circulatory dysfunction in sepsis.

This is in part due to a redistribution of intravascular fluid volume resulting from
reduced arterial vascular tone (leading to increased capillary pressure) and
increased endothelial permeability. Other changes that occur include venous
dilation (thereby diminishing venous return to the heart) and the release of
myocardial depressant substances [12]. When hypotension complicates sepsis,
anomalies in the distribution of flow at the regional and microregional circulation
are accentuated, thereby accelerating the progression of tissue injury.

The lung — Endothelial injury in the pulmonary vasculature leads to disturbed

capillary blood flow and enhanced microvascular permeability, resulting in
interstitial and alveolar edema [13,14]. Neutrophil entrapment within the lung's
microcirculation initiates and/or amplifies this injury to the alveolocapillary
membrane. Pulmonary edema is the clinical consequence, and is accompanied by
ventilation-perfusion mismatch and arterial hypoxemia. The prominence of the
lung injury that is often seen in sepsis probably reflects its large microvascular
surface area. The acute respiratory distress syndrome is a frequent manifestation of
these effects. (See "Acute respiratory distress syndrome: Pathophysiology; clinical
manifestations; and prognosis").

The gastrointestinal tract — The gastrointestinal tract is a particularly important

target organ system for injury in sepsis since it has the potential to provide a
positive feedback loop in propagation of the injury. Particularly when the septic
patient is intubated and unable to eat, bacteria may overgrow the upper
gastrointestinal tract and may be aspirated into the lungs, producing a nosocomial
pneumonia. Furthermore, the circulatory abnormalities typical of sepsis may
depress the gut's normal barrier function, allowing translocation of bacteria and
endotoxin into the systemic circulation (possibly via lymphatics, rather than the
portal vein) and extending the septic response [13,14,15]. Confirming suggestions
from animal models of sepsis, a prospective observational cohort study concluded
that increased intestinal permeability prior to the onset of MODS (determined from
the urinary excretion of orally administered lactulose and mannose) was predictive
of the development of MODS [16].

The liver — By virtue of the liver's role in host defense and synthetic functions,
liver dysfunction can contribute to both the initiation and progression of sepsis.
The reticuloendothelial system of the liver normally acts as the first line of defense
in clearing bacteria and bacteria-derived products that have entered the portal
system from the gut. Liver dysfunction can prevent the elimination of enteric-
derived endotoxin and bacteria-derived products, which precludes the appropriate
local cytokine response and permits direct spillover of these potentially injurious
products into the systemic circulation [13,14].

The kidney — Sepsis is often accompanied by acute renal failure due to acute
tubular necrosis [13,14]. The mechanisms by which sepsis and endotoxinemia
might lead to acute renal failure are incompletely understood. Systemic
hypotension, direct renal vasoconstriction, release of cytokines such as tumor
necrosis factor, and activation of neutrophils by endotoxin and by FMLP, a three
amino acid (fMet-Leu-Phe) chemotactic peptide in bacterial cell walls, all may
contribute to renal injury. (See "Postischemic and postoperative acute tubular

The likelihood of death is increased in patients with sepsis who develop renal
failure. Why this occurs is not well understood. One factor that may contribute is
the release of proinflammatory mediators as a result of leukocyte-dialysis
membrane interactions when hemodialysis is necessary. Use of biocompatible
membranes can prevent these interactions and may improve survival and the
recovery of renal function [17]. (See "Dialysis in acute renal failure: Indications
and dialysis prescription", section on Complement activation).

The nervous system — Involvement of the central nervous system in sepsis can
produce an altered sensorium (encephalopathy) and a peripheral neuropathy
[13,14]. The pathogenesis of the encephalopathy is poorly defined. Although a
high incidence of brain microabscesses was noted in one study, the significance of
hematogenous infection as the principal mechanism has been questioned because
of considerable heterogeneity in the observed pathology.


— Normal inflammation involves the regulation of PMN rolling, adhesion,
diapedesis, chemotaxis, phagocytosis, and killing of invading bacteria. These
processes are highly controlled, with regulation through pro- and anti-
inflammatory cytokines released by activated macrophages [18,19,20]. When
sepsis occurs, these actions may lead to remote tissue injury.

The important proinflammatory cytokines include TNF-alpha (TFNa) and IL-1,

which share a remarkable array of biological effects (show table 1). Evidence
supporting a role for TNFa in sepsis includes the following:

• Circulating TNFa levels are elevated in septic patients [21]. This may be due in
part to the binding of endotoxin to LPS-binding protein and its subsequent transfer
to CD14 on macrophages, which stimulates the release of TNFa [22].

• TNFa infusion produces symptoms similar to those observed in septic shock


• Anti-TNFa antibodies protects animals from lethal challenge with endotoxin


Several cytokines, referred to as antiinflammatory cytokines, inhibit the production

of TNFa and IL-1; however, their effects are not universally antiinflammatory.
Examples include IL- 10 and IL-6, both of which have the following actions [25]:

• They stimulate the immune system by enhancing B cell function (proliferation,

immunoglobulin secretion) and encouraging the development of cytotoxic T cells.

• They suppress the immune system by inhibiting cytokine production by

mononuclear cells and monocyte-dependent T helper cells.

Bacterial factors — Direct effects of invading microorganisms or their toxic

products may also contribute to the pathogenesis of sepsis. Among the potentially
offending factors are endotoxin, cell wall components of bacteria (peptidoglycan,
muramyl dipeptide, and lipoteichoic acid), and bacterial products such as
staphylococcal enterotoxin B, toxic shock syndrome toxin-1, Pseudomonas
exotoxin A, and M protein of hemolytic group A streptococci [26].
There is substantial evidence to suggest that endotoxin is an important exogenous
mediator of sepsis in gram negative bacterial infections. Endotoxin, a
lipopolysaccharide found in the cell wall of gram negative bacteria, tends to
reproduce many of the features of sepsis when infused in humans [27]. The
coagulation, complement, and contact and fibrinolytic systems are all activated by
endotoxin. This may lead to the production of vasoactive products (such as
bradykinin) and to complement activation, both of which can enhance endothelial
permeability. Complement activation and disruption of the normal
coagulation/lysis equilibrium can also lead to microvascular thrombosis.

Endotoxemia is detectable in septic patients. Furthermore, elevated plasma levels

of endotoxin are associated with shock and multiple organ dysfunction (show table


mechanisms of cell injury and resulting organ dysfunction in sepsis are not fully
understood. Autopsy studies show that multiple organ dysfunction syndrome, the
common precursor of death in sepsis, is associated with widespread endothelial
and parenchymal cell injury. Mechanisms proposed to explain these findings

• Ischemia (oxygen lack relative to oxygen need),

• Cytopathic injury (direct cell injury by proinflammatory mediators and/or other
products of inflammation)
• An increased rate of apoptosis (programmed cell death).

Hypoxic hypoxia — The septic microcirculatory lesion disrupts tissue

oxygenation, suggesting that disturbances in the metabolic regulation of tissue
oxygen delivery contribute to the pathogenesis of organ dysfunction. As noted
above, both microvascular and endothelial abnormalities contribute to the septic
microcirculatory defect in sepsis. (See "ATS guidelines: Tissue hypoxia: How to
detect; how to correct; how to prevent").

An interaction between endothelial cells and PMNs is directly involved in this

uncontrolled inflammatory state in sepsis. The increase in receptor-mediated
neutrophil-endothelial cell adherence results in the secretion of reactive oxygen
species, lytic enzymes, and vasoactive substances (nitric oxide, endothelin,
platelet-derived growth factor, and platelet activating factor) into the extracellular
milieu. The ensuing microcirculatory injury leads to impaired cellular oxygen
diffusion, due to a reduction in the cross-sectional area available for tissue oxygen

Another contributing factor in sepsis is that erythrocytes lose their normal ability to
deform within the systemic microcirculation. "Rigid" erythrocytes find it difficult
to navigate the septic microcirculation. These combined microcirculatory events,
including reduction of surface area available for gas exchange, cause excessive
heterogeneity in microcirculatory blood flow and depressed tissue oxygen flux.

Direct cytotoxicity — Cell culture experiments have shown that the cytotoxicity of
endotoxin, TNFa, and nitric oxide involves direct damage to mitochondrial
electron transport. This functional change is accompanied by degeneration of the
mitochondrial ultrastructure, which precedes measurable changes in other cellular
organelles by several hours. The net effect is that disordered energy metabolism in
sepsis may be partly due to structural disruption of electron transport as a result of
destruction or dysfunction of both inner membrane and matrix proteins.

In preclinical studies, evidence for the concept of cytopathic hypoxia is seen in

experiments where ileomucosal PO2 was not low, but actually supranormal, in
well-resuscitated endotoxemic pigs [28]. Similar findings were reported in another
animal model, where oxygen tension was found to be elevated in the bladder
epithelium of endotoxemic rats [29]. Interestingly, in a clinical study, skeletal
muscle PO2 was reported to decrease (relative to normal values) in patients with
cardiogenic shock, but actually increased in acidemic patients with septic shock
[30]. Thus, cell injury and death in sepsis may be explained by cytopathic (or
histotoxic) anoxia, an inability to utilize oxygen even when present.

Apoptosis — Apoptosis (programmed cell death) describes a set of regulated

physiologic and morphologic changes leading to cellular death. This is the
principal mechanism by which senescent or dysfunctional cells are normally
eliminated. In addition, cell death via apoptosis is the dominant process leading to
the termination of inflammation once infection has subsided. However,
proinflammatory cytokines may delay apoptosis in activated macrophages and
neutrophils. This effect may prolong or augment the inflammatory response,
thereby contributing to the development of multiple organ failure.

Derangements of apoptotic cell death are also believed to play a critical role in the
tissue injury of sepsis [31]. As an example, apoptosis is normally a physiologic
mechanism to selectively limit cell populations with rapid proliferation (eg, gut
epithelium). When exposed to various inflammatory mediators, such as endotoxin,
cytokines, and reactive oxygen species, parenchymal and endothelial cells respond
by the induction of one of two programs of stress gene expression. When
subsequently exposed to endotoxin, these cells undergo accelerated apoptosis.

From excessive proinflammatory response to immunosuppression — The

interaction between proinflammatory and antiinflammatory mediators can be
viewed as a struggle between opposing influences. Different scenarios can
plausibly result from the combined effects of the sepsis syndrome and the host's
compensatory antiinflammatory response to it [3]:

• If the mediators balance each other and the initial infectious insult is overcome,
homeostasis will be restored.

• The initial insult may be so severe that it is sufficient to directly induce SIRS
and multiple organ dysfunction.

• In most patients who survive the initial insult, a balance between

proinflammatory and antiinflammatory processes is not established, and a massive
systemic inflammatory response and/or an antiinflammatory reaction may ensue. A
wide range of clinical sequelae may occur in which either SIRS or an
antiinflammatory reaction ("immune paralysis" or a "window of
immunodeficiency") predominates, or both may be present (show figure 4).

What is a Premature Birth?

Health care providers consider labor to be preterm if it starts before 37 weeks of pregnancy.
Because a fetus is not fully grown at 37 weeks, and it may not be able to survive outside
the womb, health care providers will often take steps to stop labor if it starts before this
time. Common methods for trying to stop labor include bed rest and medications that relax
the muscles in the uterus involved with labor and delivery.

A premature birth is also called a preterm labor.

Symptoms of a Premature Birth

Some of the common symptoms of a premature birth are:

• Contractions every 10 minutes or more often (they don't have to be painful)

• Clear, pink or brownish fluid (water) leaking from your vagina
• Pelvic pressure—the feeling that your baby is pushing down
• Low, dull backache
• Cramps that feel like your period
• Abdominal cramps, with or without diarrhea

If you believe you are about to give birth to a premature child, call your doctor or go to the
hospital immediately.

Complications of a Premature Birth

Premature infants face a number of health challenges. Some of the common health
challenges include low birth weight, breathing problems, and underdeveloped organs and
organ systems. Many infants that are born prematurely need to stay in the hospital until
their health is stable, sometimes several weeks or more.

Breathing Difficulty of a Premature Baby

Premature babies usually will cry only softly, if at all, and may have trouble breathing. They
have trouble breathing because her respiratory system is not fully developed. If the baby is
more than two months early, its breathing difficulties can cause serious health problems,
because the other organs in her body may not get enough oxygen. If the baby needs help
breathing, it may be given extra oxygen, or special equipment may be used temporarily to
do some of her breathing for her.

Characteristics of Premature Babies

A baby that is born prematurely may neither look nor behave like a full-term infant. While
the average full-term baby weighs about 7 pounds at birth, a premature newborn might
weigh 5 pounds or even less. The earlier the baby arrives, the smaller the baby will be, the
larger her head will seem in relation to the rest of her body, and the less fat she will have.

After a quick examination in the delivery room, the baby will probably be moved to a
special-care nursery.